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Review
. 2024 May 10;16(10):1819.
doi: 10.3390/cancers16101819.

FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets

Debora Capelli  1
Affiliations
Review

FLT3-Mutated Leukemic Stem Cells: Mechanisms of Resistance and New Therapeutic Targets

Debora Capelli. Cancers (Basel). .

Abstract

Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation of glycogen synthesis, inhibition of the RAS/MAPK pathway, and degradation of FLT3 may be potential aids to fight the resistance of LSC to FLT3i. LSC is also characterized by the expression of a CD34+/CD25+/CD123+/CD99+ immunophenotype. The receptor and ligand of FLT3, the natural killer group 2 member D ligand (NKGD2L), and CD123 are some of the targets of chimeric antigen receptor T cells (CAR-T), bispecific T-cell engager molecules (BiTEs), CAR-NK and nanoparticles recently designed and reported here. The combination of these new therapeutic options, hopefully in a minimal residual disease (MRD)-driven approach, could provide the future answer to the challenge of treating FLT3mut AML.

Keywords: CAR-NK; CAR-T; FLT3 inhibitors; FLT3-mutated AML; immunotherapy; leukemic stem cell mechanisms of resistance; leukemic stem cell metabolism; leukemic stem cells molecular pathways.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
LSC metabolism and interaction with stroma.
Figure 2
Figure 2
Molecular pathways promoting stemness and survival of LSC.
Figure 3
Figure 3
Scheme of ‘old’ and new CAR-T constructs.
See this image and copyright information in PMC

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